Quantitative Analysis of Dynamic Allostery

Abstract

Dynamic allostery refers to one important class of allosteric regulation that does not involve noticeable conformational changes upon effector binding. In recent years, many “quasi”-dynamic allosteric proteins have been found to only experience subtle conformational changes during allosteric regulation. However, as enthalpic and entropic contributions are coupled to each other and even tiny conformational changes could bring in noticeable free energy changes, a quantitative description is essential to understand the contribution of pure dynamic allostery. Here, by developing a unified anisotropic elastic network model (uANM) considering both side-chain information and ligand heavy atoms, we quantitatively estimated the contribution of pure dynamic allostery in a dataset of known allosteric proteins by excluding the conformational changes upon ligand binding. We found that the contribution of pure dynamic allostery is generally small (much weaker than previously expected) and robustly exhibits an allosteric activation effect, which exponentially decays with the distance between the substrate and the allosteric ligand. We further constructed toy models to study the determinant factors of dynamic allostery in monomeric and oligomeric proteins using the uANM. Analysis of the toy models revealed that a short distance, a small angle between the two ligands, strong protein–ligand interactions, and weak protein internal interactions lead to strong dynamic allostery. Our study provides a quantitative estimation of pure dynamic allostery and facilitates the understanding of dynamic-allostery-controlled biological processes and the design of allosteric drugs and proteins.

Dynamically driven correlations in elastic net models reveal sequence of events and causality in proteins

“…Along the same lines, Scaramozzino et al 16,17 extended the Langevin equation solution to the ANM, and analyzed protein fluctuations in response to random external forces, validating our previous results 18 for the GNM. ANM was used for a quantitative analysis of dynamic allostery by Huang et al 19 In summary, our study contributes to the understanding of allosteric information transfer in proteins and highlights the importance of considering spatial heterogeneity and viscosity in modeling protein dynamics. Thus, the isotropic GNM serves as the zeroth order approximation to the problem of allosteric information transfer in proteins, laying the groundwork for further refinements and improvements.…”

“…Along the same lines, Scaramozzino et al 16,17 extended the Langevin equation solution to the ANM, and analyzed protein fluctuations in response to random external forces, validating our previous results 18 for the GNM. ANM was used for a quantitative analysis of dynamic allostery by Huang et al 19 …”

Dynamics-Based Regulatory Switches of Type II Antitoxins: Insights into New Antimicrobial Discovery

“…The propagation between the distant binding sites can be interpreted as a relay of change in protein dynamics and flexibility, known as dynamic allostery [ 50 ], or within defined sets of visible conformations. We believe that the presence of multiple antitoxin-binding sites on the operator adds multiple levels of the complexity to the cooperative repression/de-repression mechanism for TA transcription.…”

RNA’s Dynamic Conformational Selection and Entropic Allosteric Mechanism in Controlling Cascade Protein Binding Events

“…Interest in RNA’s allosteric mechanisms , has recently surged, especially concerning its role in various biological processes such as RNA viruses, bacterial RNA regulation, and the emergence of RNA vaccines. − Similar to allosteric proteins, allosteric RNAs − control their activities through effector binding at a distant site, affecting functions like ligand binding, , RNA splicing, riboswitch regulation, , and ribozyme activities. − This communication was traditionally thought to involve significant conformational transitions, thereby shifting the free energy basin of the conformational state . Alternatively, it is plausible that the conformation induced by effector binding simply alters the broadness of the free energy minimum without substantially changing the position of the basin in the conformational phase space, a concept now recognized as dynamic allostery. − However, contrasting two RNA systems (BIV and HIV TAR–TAT complexes), this study reveals that effector-driven allostery can be either entropic or enthalpic. In either case, distant communication (loop and bulge interactions) is mediated by rewiring base connections with a marginal backbone deformation.…”